Genome-wide association (GWA) studies of colorectal cancer (CRC) have led to the identification of a number of significantly associated hits that have been robustly replicated in other populations. The number of associations is likely to grow considerably over the next few years as larger GWA studies of CRC using higher density SNP arrays as well as meta- or pooled analyses of existing GWA studies are completed. To date there has been little emphasis on identifying the causal variant associated with these findings and even less effort directed towards developing an understanding of their biological impact. Without conducting studies designed to characterize the functional relevance of causal variants identified through GWA studies a complete understanding of the biological implications of such approaches will not be achieved. The goal of this proposal is to develop comprehensive strategies for the functional analysis of hits arising from CRC GWA studies using a multidisciplinary approach. This is not an insignificant challenge as most of the associations identified to date through GWA studies do not target non-synonymous variants in exons but instead involve variants that lie near genes or within gene-poor regions that require comprehensive analytical approaches. We will pursue validated hits arising from published CRC GWA studies by developing fine mapping information across these regions. We will incorporate state-of-the-art barcoded multiplex deep re-sequencing, and leverage information from ChIP-seq, RNA-seq and in silico analyses to identify candidate causal variants in genic or regulatory regions that will be functionally tested using biochemical analyses. Our goal is to identify the causal gene(s) identified through GWA studies and to characterize the functional significance of the causal variants. By doing so we aim to fully exploit the promise of GWA studies and provide a framework for a comprehensive understanding of the biological implications of associations identified through genome wide association (GWA) studies. Our work is motivated by the growing roadblock to fully exploiting the biological significance of GWA studies and if successful our approaches should be applicable to novel associations identified in ongoing GWA studies of CRC but also other complex genetic diseases. PUBLIC HEALTH RELEVANCE: The goal of our proposal is to develop comprehensive strategies for the functional analysis of hits arising from CRC genome wide association (GWA) studies using a multidisciplinary approach. Our work is motivated by the growing roadblock to fully exploiting the biological significance of GWA studies and if successful our approaches should be applicable to novel associations identified in ongoing GWA studies of CRC but also other complex genetic diseases.